Heterocyclic compounds useful as malonyl-CoA decarboxylase inhibitors

ABSTRACT

The present invention provides methods for the use of compounds as depicted by structure I, pharmaceutical compositions containing the same, and methods for the prophylaxis, management and treatment of metabolic diseases and diseases modulated by MCD inhibition. The compounds disclosed in this invention are useful for the prophylaxis, management and treatment of diseases involving in malonyl-CoA regulated glucose/fatty acid metabolism pathway. In particular, these compounds and pharmaceutical composition containing the same are indicated in the prophylaxis, management and treatment of cardiovascular diseases, diabetes, cancer and obesity.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/492,030, filed Aug. 1, 2003.

FIELD OF THE INVENTION

The present invention relates to methods of treatment of certainmetabolic diseases and the use of compounds and their prodrugs, and/orpharmaceutically acceptable salts, pharmaceutical compositionscontaining such compounds useful in treating such diseases. Inparticular, the invention relates to the use of compounds andcompositions for the prophylaxis, management or treatment ofcardiovascular diseases, diabetes, cancers, and obesity through theinhibition of malonyl-coenzyme A decarboxylase (malonyl-CoAdecarboxylase, MCD).

BACKGROUND OF THE INVENTION

Malonyl-CoA is an important metabolic intermediary produced by theenzyme Acetyl-CoA Carboxylase (ACC) in the body. In the liver,adipocytes, and other tissues, malonyl-CoA is a substrate for fatty acidsynthase (FAS). ACC and malonyl-CoA are found in skeletal muscle andcardiac muscle tissue, where fatty acid synthase levels are low. Theenzyme malonyl-CoA decarboxylase (MCD, EC 4.1.1.9) catalyzes theconversion of malonyl-CoA to acetyl-CoA and thereby regulatesmalonyl-CoA levels. MCD activity has been described in a wide array oforganisms, including prokaryotes, birds, and mammals. It has beenpurified from the bacteria Rhizobium trifolii (An et al., J. Biochem.Mol. Biol. 32:414-418(1999)), the uropygial glands of waterfowl(Buckner, et al., Arch. Biochem. Biophys 177:539(1976); Kim andKolattukudy Arch. Biochem. Biophys 190:585(1978)), rat livermitochondria (Kim and Kolattukudy, Arch. Biochem. Biophys.190:234(1978)), rat mammary glands (Kim and Kolattukudy, Biochim.Biophys, Acta 531:187(1978)), rat pancreatic β-cell (Voilley et al.,Biochem. J. 340:213 (1999)) and goose (Anser anser) (Jang et al., J.Biol. Chem. 264:3500 (1989)). Identification of patients with MCDdeficiency lead to the cloning of a human gene homologous to goose andrat MCD genes (Gao et al., J. Lipid. Res. 40:178 (1999); Sacksteder etal., J. Biol. Chem. 274:24461(1999); FitzPatrick et al., Am. J. Hum.Genet. 65:318(1999)). A single human MCD mRNA is observed by NorthernBlot analysis. The highest mRNA expression levels are found in muscleand heart tissues, followed by liver, kidney and pancreas, withdetectable amounts in all other tissues examined.

Malonyl-CoA is a potent endogenous inhibitor of carnitinepalmitoyltransferase-I (CPT-I), an enzyme essential for the metabolismof long-chain fatty acids. CPT-I is the rate-limiting enzyme in fattyacid oxidation and catalyzes the formation of acyl-carnitine, which istransported from the cytosol across the mitochondrial membranes by acylcarnitine translocase. Inside of the mitochondria the long-chain fattyacids are transferred back to CoA form by a complementary enzyme,CPT-II, and, in the mitochondria, acyl-CoA enters the β-oxidationpathway generating acetyl-CoA. In the liver, high levels of acetyl-CoAoccurs for example following a meal, leading to elevated malonyl-CoAlevels, which inhibit CPT-I, thereby preventing fat metabolism andfavoring fat synthesis. Conversely, low malonyl-CoA levels favor fattyacid metabolism by allowing the transport of long-chain fatty acids intothe mitochondria. Hence, malonyl-CoA is a central metabolite that playsa key role in balancing fatty acid synthesis and fatty acid oxidation(Zammit, Biochem. J. 343:5050-515(1999)). Recent work indicates that MCDis able to regulate cytoplasmic as well as mitochondrial malonyl-CoAlevels [Alam and Saggerson, Biochem J. 334:233-241(1998); Dyck et al.,Am J Physiology 275:H2122-2129(1998)].

Although malonyl-CoA is present in muscle and cardiac tissues, only lowlevels of FAS have been detected in these tissues. It is believed thatthe role of malonyl-CoA and MCD in these tissues is to regulate fattyacid metabolism. This is achieved via malonyl-CoA inhibition of muscle(M) and liver (L) isoforms of CPT-I, which are encoded by distinct genes(McGarry and Brown, Eur. J. Biochem. 244:1-14(1997)). The muscle isoformis more sensitive to malonyl-CoA inhibition (IC50 0.03 μM) than theliver isoform (IC₅₀ 2.5 μM). Malonyl-CoA regulation of CPT-I has beendescribed in the liver, heart, skeletal muscle and pancreatic μ-cells.In addition, malonyl-CoA sensitive acyl-CoA transferase activity presentin microsomes, perhaps part of a system that delivers acyl groups intothe endoplasmic reticulum, has also been described (Fraser et al., FEBSLett. 446:69-74(1999)).

Cardiovascular Diseases

The healthy human heart utilizes available metabolic substrates. Whenblood glucose levels are high, uptake and metabolism of glucose providethe major source of fuel for the heart. In the fasting state, lipids areprovided by adipose tissues, and fatty acid uptake and metabolism in theheart down regulate glucose metabolism. The regulation of intermediarymetabolism by serum levels of fatty acid and glucose comprises theglucose-fatty acid cycle (Randle et al., Lancet, 1:785-789(1963)). Underischemic conditions, limited oxygen supply reduces both fatty acid andglucose oxidation and reduces the amount of ATP produced by oxidativephosphorylation in the cardiac tissues. In the absence of sufficientoxygen, glycolysis increases in an attempt to maintain ATP levels and abuildup of lactate and a drop in intracellular pH results. Energy isspent maintaining ion homeostasis, and myocyte cell death occurs as aresult of abnormally low ATP levels and disrupted cellular osmolarity.Additionally, AMPK, activated during ischemia, phosphorylates and thusinactivates ACC. Total cardiac malonyl-CoA levels drop, CPT-I activitytherefore is increased and fatty acid oxidation is favored over glucoseoxidation. The beneficial effects of metabolic modulators in cardiactissue are the increased efficiency of ATP/mole oxygen for glucose ascompared to fatty acids and more importantly the increased coupling ofglycolysis to glucose oxidation resulting in the net reduction of theproton burden in the ischemic tissue.

A number of clinical and experimental studies indicate that shiftingenergy metabolism in the heart towards glucose oxidation is an effectiveapproach to decreasing the symptoms associated with cardiovasculardiseases, such as but not limited, to myocardial ischemia (Hearse,“Metabolic approaches to ischemic heart disease and its management”,Science Press). Several clinically proven anti-angina drugs includingperhexiline and amiodarone inhibit fatty acid oxidation via inhibitionof CPT-I (Kennedy et al., Biochem. Pharmacology, 52: 273 (1996)). Theantianginal drugs ranolazine, currently in Phase III clinical trials,and trimetazidine are shown to inhibit fatty acid μ-oxidation (McCormacket al., Genet. Pharmac. 30:639(1998), Pepine et al., Am. J. Cardiology84:46 (1999)). Trimetazidine has been shown to specifically inhibit thelong-chain 3-ketoactyl CoA thiolase, an essential step in fatty acidoxidation. (Kantor et al., Circ. Res. 86:580-588 (2000)).Dichloroacetate increases glucose oxidation by stimulating the pyruvatedehydrogenase complex and improves cardiac function in those patientswith coronary artery diseases (Wargovich et al., Am. J. Cardiol.61:65-70 (1996)). Inhibiting CPT-I activity through the increasedmalonyl-CoA levels with MCD inhibitors would result in not only a novel,but also a much safer method, as compared to other known small moleculeCPT-I inhibitors, to the prophylaxis and treatment of cardiovasculardiseases.

Most of the steps involved in glycerol-lipid synthesis occur on thecytosolic side of liver endoplasmic reticulum (ER) membrane. Thesynthesis of triacyl glycerol (TAG) targeted for secretion inside the ERfrom diacyl gycerol (DAG) and acyl CoA is dependent upon acyl CoAtransport across the ER membrane. This transport is dependent upon amalonyl-CoA sensitive acyl-CoA transferase activity (Zammit, Biochem. J.343:505(1999) Abo-Hashema, Biochem. 38: 15840 (1999) and Abo-Hashema, J.Biol. Chem. 274:35577 (1999)). Inhibition of TAG biosynthesis by a MCDinhibitor may improve the blood lipid profile and therefore reduce therisk factor for coronary artery disease of patients.

Diabetes

Two metabolic complications most commonly associated with diabetes arehepatic overproduction of ketone bodies (in NIDDM) and organ toxicityassociated with sustained elevated levels of glucose. Inhibition offatty acid oxidation can regulate blood-glucose levels and amelioratesome symptoms of type II diabetes. Malonyl-CoA inhibition of CPT-I isthe most important regulatory mechanism that controls the rate of fattyacid oxidation during the onset of the hypoinsulinemic-hyperglucagonemicstate. Several irreversible and reversible CPT-I inhibitors have beenevaluated for their ability to control blood glucose levels and they areall invariably hypoglycemic (Anderson, Current Pharmaceutical Design4:1(1998)). A liver specific and reversible CPT-inhibitor, SDZ-CPI-975,significantly lowers glucose levels in normal 18-hour-fasted nonhumanprimates and rats without inducing cardiac hypertrophy (Deems et al.,Am. J. Physiology 274:R524 (1998)). Malonyl-CoA plays a significant roleas a sensor of the relative availability of glucose and fatty acid inpancreatic μ-cells, and thus links glucose metabolism to cellular energystatus and insulin secretion. It has been shown that insulinsecretagogues elevate malonyl-CoA concentration in β-cells (Prentki etal., Diabetes 45:273 (1996)). Treating diabetes directly with CPT-Iinhibitors has, however, resulted in mechanism-based hepatic andmyocardial toxicities. MCD inhibitors that inhibit CPT-I through theincrease of its endogenous inhibitor, malonyl-CoA, are thus safer andsuperior as compared to CPT-I inhibitors for treatment of diabeticdiseases.

Cancers

Malonyl-CoA has been suggested to be a potential mediator ofcytotoxicity induced by fatty-acid synthase inhibition in human breastcancer cells and xenografts (Pizer et al., Cancer Res. 60:213 (2000)).It is found that inhibition of fatty acid synthase using antitumorantibiotic cerulenin or a synthetic analog C75 markedly increase themalonyl-CoA levels in breast carcinoma cells. On the other hand, thefatty acid synthesis inhibitor, TOFA (5-(tetradecyloxy)-2-furoic acid),which only inhibits at the acetyl-CoA carboxylase (ACC) level, does notshow any antitumor activity, while at the same time the malonyl-CoAlevel is decreased to 60% of the control. It is believed that theincreased malonyl-CoA level is responsible for the antitumor activity ofthese fatty acid synthase inhibitors. Regulating malonyl-CoA levelsusing MCD inhibitors thus constitutes a valuable therapeutic strategyfor the treatment of cancer diseases.

Obesity

It is suggested that malonyl-CoA may play a key role in appetitesignaling in the brain via the inhibition of the neuropepetide Y pathway(Loftus et al., Science 288:2379(2000)). Systemic orintracerebroventricular treatment of mice with fatty acid synthase (FAS)inhibitor cerulenin or C75 led to inhibition of feeding and dramaticweight loss. It is found that C75 inhibited expression of the prophagicsignal neuropeptide Y in the hypothalamus and acted in aleptin-independent manner that appears to be mediated by malonyl-CoA.Therefore control of malonyl-CoA levels through inhibition of MCDprovides a novel approach to the prophylaxis and treatment of obesity.

Additionally, these compounds are also useful as a diagnostic tool fordiseases associated with MCD deficiency or malfunctions.

SUMMARY OF THE INVENTION

The present invention provides methods for the use of compounds asdepicted by structure I, pharmaceutical compositions containing thesame, and methods for the prophylaxis, management and treatment ofmetabolic diseases and diseases modulated by MCD inhibition. Thecompounds disclosed in this invention are useful for the prophylaxis,management and treatment of diseases involving in malonyl-CoA regulatedglucose/fatty acid metabolism pathway. In particular, these compoundsand pharmaceutical composition containing the same are indicated in theprophylaxis, management and treatment of cardiovascular diseases,diabetes, cancer and obesity.

The present invention also includes within its scope diagnostic methodsfor the detection of diseases associated with MCD deficiency ormalfunctions.

The compounds useful in the present invention are represented by thefollowing structures:

Wherein R₁, R₂, R₃, R4, X, Y and Z are as defined below. Also includedwithin the scope of these compounds are the corresponding enantiomers,diastereoisomers, prodrugs, and pharmaceutically acceptable salts. Otheraspects of this invention will become apparent as the description ofthis invention continues. Hence, the foregoing merely summarizes certainaspects of the invention and is not intended, nor should it beconstrued, as limiting the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description of the invention that follows is not intendedto be exhaustive or to limit the invention to the precise detailsdisclosed. It has been chosen and described to best explain the detailsof the invention to others skilled in the art.

The compounds useful in the present invention are represented by thefollowing formulae (I):

whereinR₁ and R₂ are independently selected from hydrogen, halogen, C₁-C₆substituted alkyl, C₁-C₆ substituted alkenyl, C₁-C₆ substituted alkynyl,alkoxyl, phenyl, substituted phenyl, aryl, heteroaryl, substitutedheteroaryl, —NHCONR₅R₆, —COR₅, —CONR₅R₆, —S(O)_(n)R₅, or —SO₂NR₅R₆;R₃ and R4 are independently selected from hydrogen, bromo, chloro,fluoro, iodo, hydroxyl, methoxyl, —COOH, —COOR₅, —NHCONR₅R₆, —COR₅,—CONR₅R₆, —S(O)_(n)R₅, or —SO₂NR₅R₆, C₁-C₆ alkyl, substituted C₁-C₆alkyl, C₁-C₆ alkoxyl, phenyl, substituted phenyl, aryl or heteroaryl;R₅ and R₆ are independently selected from hydrogen, C₁-C₆ alkyl,substituted C₁-C₆ alkyl, phenyl, substituted phenyl, aryl or heteroaryl;X is chosen form O, N, NH, NR₅, S, or C;its corresponding enantiomers, diastereoisomers or tautomers, or apharmaceutically acceptable salt, or a prodrug thereof in anpharmaceutically-acceptable carrier.

Preferably, the compounds in the present invention are represented bythe following formulae (Ia-If):

wherein R₁, R₂, R₃ and R4 are as defined above.More preferably, the compounds in the present invention are representedby the general formulae Ie

wherein R₁, R₂, R₃ and R4 are as defined above.CompositionsThe compositions of the present invention comprise:

-   (a) a safe and therapeutically effective amount of an MCD inhibiting    compound I or II, its corresponding enantiomer, diastereoisomer or    tautomer, or pharmaceutically acceptable salt, or a prodrug thereof;    and-   (b) a pharmaceutically-acceptable carrier.

As discussed above, numerous diseases can be mediated by MCD relatedtherapy.

Accordingly, the compounds useful in this invention can be formulatedinto pharmaceutical compositions for use in prophylaxis, management andtreatment of these conditions. Standard pharmaceutical formulationtechniques are used, such as those disclosed in Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

A “safe and therapeutically effective amount” of a compound useful inthe present invention is an amount that is effective, to inhibit MCD atthe site(s) of activity, in a subject, a tissue, or a cell, andpreferably in an animal, more preferably in a mammal, without undueadverse side effects (such as toxicity, irritation, or allergicresponse), commensurate with a reasonable benefit/risk ratio, when usedin the manner of this invention. The specific “safe and therapeuticallyeffective amount” will, obviously, vary with such factors as theparticular condition being treated, the physical condition of thepatient, the duration of treatment, the nature of concurrent therapy (ifany), the specific dosage form to be used, the carrier employed, thesolubility of the compound therein, and the dosage regimen desired forthe composition.

In addition to the selected compound useful for the present invention,the compositions of the present invention contain apharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Pharmaceutically-acceptablecarriers must, of course, be of sufficiently high purity andsufficiently low toxicity to render them suitable for administrationpreferably to an animal, preferably mammal being treated.

Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4. In particular, pharmaceutically-acceptablecarriers for systemic administration include sugars, starches, celluloseand its derivatives, malt, gelatin, talc, calcium sulfate, vegetableoils, synthetic oils, polyols, alginic acid, phosphate buffer solutions,emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriersfor parenteral administration include propylene glycol, ethyl oleate,pyrrolidone, ethanol, and sesame oil. Preferably, thepharmaceutically-acceptable carrier, in compositions for parenteraladministration, comprises at least about 90% by weight of the totalcomposition.

The compositions of this invention are preferably provided in unitdosage form. As used herein, a “unit dosage form” is a composition ofthis invention containing an amount of a compound that is suitable foradministration to an animal, preferably mammal subject, in a singledose, according to good medical practice. (The preparation of a singleor unit dosage form however, does not imply that the dosage form isadministered once per day or once per course of therapy. Such dosageforms are contemplated to be administered once, twice, thrice or moreper day, and are expected to be given more than once during a course oftherapy, though a single administration is not specifically excluded.The skilled artisan will recognize that the formulation does notspecifically contemplate the entire course of therapy and such decisionsare left for those skilled in the art of treatment rather thanformulation.) These compositions preferably contain from about 5 mg(milligrams), more preferably from about 10 mg to about 1000 mg, morepreferably to about 500 mg, most preferably to about 300 mg, of theselected compound.

The compositions useful for this invention may be in any of a variety offorms, suitable (for example) for oral, nasal, rectal, topical(including transdermal), ocular, intracereberally, intravenous,intramuscular, or parenteral administration. (The skilled artisan willappreciate that oral and nasal compositions comprise compositions thatare administered by inhalation, and made using available methodologies.)Depending upon the particular route of administration desired, a varietyof pharmaceutically-acceptable carriers well-known in the art may beused. These include solid or liquid fillers, diluents, hydrotropies,surface-active agents, and encapsulating substances. Optionalpharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms:Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms2d Edition (1976).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, and preferablyfrom about 25% to about 50%, of the compound. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carrier suitable for the preparation ofunit dosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of the subjectinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions of the subject invention may optionally include other drugactives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

The compositions of this invention can also be administered topically toa subject, e.g., by the direct application or spreading of thecomposition on the epidermal or epithelial tissue of the subject, ortransdermally via a “patch”. Such compositions include, for example,lotions, creams, solutions, gels and solids. These topical compositionspreferably comprise a safe and effective amount, usually at least about0.1%, and preferably from about 1% to about 5%, of the compound.Suitable carriers for topical administration preferably remain in placeon the skin as a continuous film, and resist being removed byperspiration or immersion in water. Generally, the carrier is organic innature and capable of having dispersed or dissolved therein thecompound. The carrier may include pharmaceutically-acceptable emollient,emulsifiers, thickening agents, solvents and the like.

Methods of Administration

The compounds and compositions useful in this invention can beadministered topically or systemically. Systemic application includesany method of introducing compound into the tissues of the body, e.g.,intra-articular, intrathecal, epidural, intramuscular, transdermal,intravenous, intraperitoneal, subcutaneous, sublingual administration,inhalation, rectal, or oral administration. The compounds useful in thepresent invention are preferably administered orally.

The specific dosage of the compound to be administered, as well as theduration of treatment is to be individualised by the treatingclinicians. Typically, for a human adult (weighing approximately 70kilograms), from about 5 mg, preferably from about 10 mg to about 3000mg, more preferably to about 1000 mg, more preferably to about 300 mg,of the selected compound is administered per day. It is understood thatthese dosage ranges are by way of example only, and that dailyadministration can be adjusted depending on the factors listed above.

In all of the foregoing, of course, the compounds useful in the presentinvention can be administered alone or as mixtures, and the compositionsmay further include additional drugs or excipients as appropriate forthe indication. For example, in the treatment of cardiovasculardiseases, it is clearly contemplated that the invention may be used inconjunction with beta-blockers, calcium antagonists, ACE inhibitors,diuretics, angiotensin receptor inhibitors, or known cardiovasculardrugs or therapies. Hence, in this example, compounds or compositionsuseful in this invention are useful when dosed together with anotheractive and can be combined in a single dosage form or composition.

These compositions can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles, and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine, orphosphatidylcholines.

DEFINITIONS

As used herein, “alkyl” means a straight chain alkane, alkene, or alkynesubstituent containing only carbon and hydrogen, such as methyl, ethyl,butyl, pentyl, heptyl and the like. Alkyl groups can be saturated orunsaturated (i.e., containing —C═C— or —C≡C— linkages), at one orseveral positions. When a specific degree of unsaturation is preferred,said substituent is referred to as either “alkenyl” or “alkynyl”,denoting substituents containing —C═C— or —C≡C— linkages, respectively.The number of carbons may be denoted as “C_(i)-C_(j)-alkyl” wherein Iand j refer to the minimum and maximum number of carbon atoms,respectively. Typically, alkyl groups will comprise 1 to 12 carbonatoms, preferably 1 to 10, and more preferably 2 to 8 carbon atoms.

As used herein, “substituted alkyl” means a hydrocarbon substituent,which is linear, cyclic or branched, in which one or more hydrogen atomsare substituted by carboxy, hydroxy, alkoxy, cyano, nitro, carbonyl,aryl, carboxyalkyl, mercapto, amino, amido, ureido, carbamoyl,sulfonamido, sulfamido, or halogen. Preferred substituted alkyls havetheir alkyl spacers (i.e., portion which is alkyl) of 1 to about 5carbons, and may be branched or linear, and may include cyclicsubstituents, either as part or all of their structure. Preferredexamples of “substituted alkyls” include 4-carboxybutyl,pyridin-2-ylmethyl, and 1,3-thiazol-2-ylmethyl, benzyl, phenethyl, andtrifluoromethyl. The term “substituted alkyl” may be combined with otherart accepted terms. For example “substituted alkoxy” means alkoxy asunderstood in the art, wherein the alkyl portion of the substituent issubstituted.

As used herein, “branched alkyl” means a subset of “alkyl”, and thus isa hydrocarbon substituent, which is branched. Preferred branched alkylsare of 3 to about 12 carbons, and may include cycloalkyl within theirstructure. Examples of branched alkyl include isopropyl, isobutyl,1,2-dimethyl-propyl, cyclopentylmethyl and the like. The term “branchedalkyl” may be combined with other art accepted terms. For example“branched alkoxy” means alkoxy as understood in the art, wherein thealkyl portion of the substituent is branched.

As used herein, “cycloalkyl” is a hydrocarbon substituent that iscyclic, and can be substituted or unsubstituted. Where it issubstituted, one or more hydrogen atoms are substituted by carboxy,hydroxy, alkoxy, cyano, nitro, carbonyl, aryl, carboxyalkyl, mercapto,amino, amido, ureido, carbamoyl, sulfonamido, sulfamido, or halogen.Preferred cyclic alkyls are of 3 to about 7 carbons. Examples ofcycloalkyl include cyclopropyl, cyclopentyl, 4-fluoro-cyclohexyl,2,3-dihydroxy-cyclopentyl, and the like.

As used herein, “alkylene” is an alkyl diradical, i.e., an alkyl thathas open valences on two different carbon atoms. Hence “(alkylene)R_(i)”is an alkyl diradical attached at one carbon and having substituentR_(i) attached at another carbon, which may be one or more carbons awayfrom the point of attachment. Alkylene can be linear, branched, orcyclic. Examples of alkylene include —CH₂—, CH₂CH₂—, —(CH₂)₄—,-(cyclohexyl)-, and the like.

As used herein, “aryl” is a substituted or unsubstituted aromatic, i.e.,Huckel 4n+2 rule applies, radical having a single-ring (e.g., phenyl) ormultiple condensed rings (e.g., naphthyl or anthryl), which may containzero to 4 heteroatoms. Hence the term “heteroaryl” is clearlycontemplated in the term “aryl”. Preferred carbocyclic aryl, is phenyl.Preferred monocyclic heterocycles, i.e., heteroaryls, are 5 or 6membered rings. Preferably, where the term “aryl” represents an aromaticheterocycle, it is referred to as “heteroaryl” or “heteroaromatic”, andhas one or more heteroatom(s). Preferred numbers of such heteroatoms arefrom one to three N atoms, and preferably when “heteroaryl” is aheterocycle of five members, it has one or two heteroatoms selected from0, N, or S. Hence, preferred heterocycles have up to three, morepreferably two or less, heteroatoms present in the aromatic ring. Theskilled artisan will recognize that among heteroaryl, there are bothfive and six membered rings. Examples of “heteroaryl” include; thienyl,pyridyl, pyrimidyl, pyridazyl, furyl, oxazolyl, imidazolyl, thiazolyl,oxadiazilyl, triazinyl, triazolyl, thiadiazolyl, and others, which theskilled artisan will recognize. In this definition it is clearlycontemplated that substitution on the aryl ring is within the scope ofthis invention. Where substitution occurs, the radical is referred to as“substituted aryl”. Preferably one to three, more preferably one or two,and most preferably one substituent is attached to the aryl ring.Although many substituents will be useful, preferred substituentsinclude those commonly found in aryl compounds, such as alkyl, hydroxy,alkoxy, cyano, nitro, halo, haloalkyl, mercapto and the like. Suchsubstituents are prepared using known methodologies. These substituentsmay be attached at various positions of the aryl ring, and wherein agiven placement is preferred, such placement is indicated by“o,m,p-R_(i)-aryl”. Thus, if substituent R_(i) is attached at the paraposition of the aryl, then this is indicated as “p-R_(i)-substitutedaryl”.

As used herein, “amide” includes both RNR′CO— (in the case of R=alkyl,alkaminocarbonyl-) and RCONR′— (in the case of R=alkyl, alkylcarbonylamino-).

As used herein, “ester” includes both ROCO— (in the case of R=alkyl,alkoxycarbonyl-) and RCOO— (in the case of R=alkyl, alkylcarbonyloxy-).

As used herein, “halogen” is a chloro, bromo, fluoro or iodo atomradical. Chloro, bromo and fluoro are preferred halogens. The term“halogen” also contemplates terms sometimes referred to as “halo” or“halide”.

As used herein, “alkylamino” is an amine radical in which at least onehydrogen atom on the nitrogen has been replaced with alkyl. Preferredexamples include ethylamino, butylamino, isopropylamino, and the like.The alkyl component may be linear, branched, cyclic, substituted,saturated, or unsaturated.

As used herein, “alkylsulfanyl” is a thiol radical in which the hydrogenatom on sulfur has been replaced with alkyl. Preferred examples includeethylsulfanyl, butylsulfanyl, isopropylsulfanyl, and the like. The alkylcomponent may be linear, branched, cyclic, substituted, saturated, orunsaturated.

As used herein, “alkoxy” is a hydoxyl radical in which the hydrogen atomon oxygen has been replaced with alkyl. Preferred examples includeethoxy, butoxy, benzyloxy, and the like. The alkyl component may belinear, branched, cyclic, substituted, saturated, or unsaturated.

As used herein, “heterocycle(s)” means ring systems, preferably of 3-7members, which are saturated or unsaturated, and non-aromatic. These maybe substituted or unsubstituted, and are attached to other parts of themolecule via any available valence, preferably any available carbon ornitrogen. More preferred heterocycles are of 5 or 6 members. Insix-membered monocyclic heterocycles, the heteroatom(s) are from one tothree of O, S, or N, and wherein when the heterocycle is five-membered,preferably it has one or two heteroatoms selected from O, N, or S.

As used herein, “heterocyclyl” means radical heterocycles. These may besubstituted or unsubstituted, and are attached to other via anyavailable valence, preferably any available carbon or nitrogen.

As used herein, “sulfamido” means an alkyl-N—S(O)₂N—, aryl-NS(O)₂N— orheterocyclyl-NS(O)₂N— group wherein the alkyl, aryl or heterocyclylgroup is as defined herein above.

As used herein, “sulfonamido” means an alkyl-S(O)₂N—, aryl-S(O)₂N— orheterocyclyl-S(O)₂N— group wherein the alkyl, aryl or heterocyclcylgroup is as herein described.

As used herein, “ureido” means an alkyl-NCON—, aryl-NCON— orheterocyclyl-NCON— group wherein the alkyl, aryl or heterocyclyl groupis as herein described.

A substituent referred to as a radical in this specification may form aring with another radical as described herein. When such radicals arecombined, the skilled artisan will understand that there are nounsatisfied valences in such a case, but that specific substitutions,for example a bond for a hydrogen, is made. Hence certain radicals canbe described as forming rings together. The skilled artisan willrecognize that such rings can and are readily formed by routine chemicalreactions, and it is within the purview of the skilled artisan to bothenvision such rings and the methods of their formations. Preferred arerings having from 3-7 members, more preferably 5 or 6 members. Compoundsdescribed herein may have cyclic structures therein, such as a ring R₁and R₂. In that regard the skilled artisan recognizes that this methodof description is routine in medicinal chemistry, though such may notrigorously reflect the chemical synthetic route. As used herein the term“ring” or “rings” when formed by the combination of two radicals refersto heterocyclic or carbocyclic radicals, and such radicals may besaturated, unsaturated, or aromatic. For example, preferred heterocyclicring systems include heterocyclic rings, such as morpholinyl,piperdinyl, imidazolyl, pyrrolidinyl, and pyridyl.

The skilled artisan will recognize that the radical of formula:

represents a number of different functionalities. Preferredfunctionalities represented by this structure include amides, ureas,thioureas, carbamates, esters, thioesters, amidines, ketones, oximes,nitroolefines, hydroxyguanidines and guanidines. More preferredfunctionalities include ureas, thioureas, amides, and carbamates.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures. The artisan recognizes thatsuch structures are clearly contemplated within the scope of thisinvention, although such resonance forms or tautomers are notrepresented herein. For example, the structures:

clearly represent the same compound(s), and reference to either clearlycontemplates the other. In addition, the compounds useful in thisinvention can be provided as prodrugs, the following of which serve asexamples:

wherein R is a group (or linkage) removed by biological processes.Hence, clearly contemplated in this invention is the use compoundsprovided as biohydrolyzable prodrugs, as they are understood in the art.“Prodrug”, as used herein is any compound wherein when it is exposed tothe biological processes in an organism, is hydrolyzed, metabolized,derivatized or the like, to yield an active substance having the desiredactivity. The skilled artisan will recognize that prodrugs may or maynot have any activity as prodrugs. It is the intent that the prodrugsdescribed herein have no deleterious effect on the subject to be treatedwhen dosed in safe and effective amounts. These include for example,biohydrolyzable amides and esters. A “biohydrolyzable amide” is an amidecompound which does not essentially interfere with the activity of thecompound, or that is readily converted in vivo by a cell, tissue, orhuman, mammal, or animal subject to yield an active compound. A“biohydrolyzable ester” refers to an ester compound that does notinterfere with the activity of these compounds or that is readilyconverted by an animal to yield an active compound. Such biohydrolyzableprodrugs are understood by the skilled artisan and are embodied inregulatory guidelines.

Compounds and compositions herein also specifically contemplatepharmaceutically acceptable salts, whether cationic or anionic. A“pharmaceutically-acceptable salt” is an anionic salt formed at anyacidic (e.g., carboxyl) group, or a cationic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987 (incorporated by reference herein). Preferred counter-ions ofsalts formable at acidic groups can include cations of salts, such asthe alkali metal salts (such as sodium and potassium), and alkalineearth metal salts (such as magnesium and calcium) and organic salts.Preferred salts formable at basic sites include anions such as thehalides (such as chloride salts). Of course, the skilled artisan isaware that a great number and variation of salts may be used, andexamples exist in the literature of either organic or inorganic saltsuseful in this manner.

Inasmuch as the compounds useful in this invention may contain one ormore stereogenic centers, “Optical isomer”, “stereoisomer”,“enantiomer,” “diastereomer,” as referred to herein have the standardart recognized meanings (cf. Hawleys Condensed Chemical Dictionary, 11thEd.) and are included in these compounds, whether as racemates, or theiroptical isomers, stereoisomers, enantiomers, and diastereomers.

As used herein, the term “metabolic disease”, means a group ofidentified disorders in which errors of metabolism, imbalances inmetabolism, or sub-optimal metabolism occur. The metabolic diseases asused herein also contemplate a disease that can be treated through themodulation of metabolism, although the disease itself may or may not becaused by specific metabolism blockage. Preferably, such metabolicdisease involves glucose and fatty acid oxidation pathway. Morepreferably, such metabolic disease involves MCD or is modulated bylevels of Malonyl CoA, and is referred to herein as an “MCD or MCArelated disorder.”

Preparation of Compounds

The starting materials used in preparing the compounds useful in thisinvention are known, made by known methods, or are commerciallyavailable. It will be apparent to the skilled artisan that methods forpreparing precursors and functionality related to the compounds claimedherein are generally described in the literature. The skilled artisangiven the literature and this disclosure is well equipped to prepare anyof these compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, reductive alkylation ofamines, oxidations, acylations, aromatic substitutions, bothelectrophilic and nucleophilic, etherifications, esterification,saponification and the like. These manipulations are discussed instandard texts such as March Advanced Organic Chemistry (Wiley), Careyand Sundberg, Advanced Organic Chemistry and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtecting Groups in Organic Synthesis, 2^(nd) Ed., John Wiley & Sons(1991).

The following example schemes are provided for the guidance of thereader, and represent preferred methods for making the compoundsexemplified herein. These methods are not limiting, and it will beapparent that other routes may be employed to prepare these compounds.Such methods specifically include solid phase based chemistries,including combinatorial chemistry. The skilled artisan is thoroughlyequipped to prepare these compounds by those methods given theliterature and this disclosure.

As shown in the above scheme, treatment of benzofuran O-methyl ether (1)with tribromoboron in dichloromethane provided the free5-hydroxybenzofuran compound 2 which coupled to primary or secondaryamine under conventional peptide coupling conditions gave rise to thedesired 2-carboxamide derivatives 3.

Scheme 2 illustrated the synthesis of C-3 carboxamides. Starting fromthe same starting material 1, bromination occurred at C-3 position inthe presence of bromine and using CS₂ as solvent. Decarboxylation of C-2carboxylic acid group was achieved under conventional condition(Cu-Quinoline) to provide 3-bromo-5-methoxy-benzofuran 5 in good yields.Compound 5 was subsequently treated with n-butyllithium followed by dryice to furnish C-3 carboxylic acid compound 6. Following the sequence inScheme 1, the intermediate compound 6 was converted into itscorresponding C-3 carboxamides 8.

Alternatively, C-2 substituted C-3 carboxamides compounds 12 could beprepared by the procedure shown in the Scheme 3 (Giza; Hinman; J. Org.Chem.; 1964, 29:1453). In the presence of Lewis acid (e.g. ZnCl2),b-diketone or b-ketoester 9 was coupled with quinone derivatives 10 toprovide the desired C2 substituted C-3 ketone derivatives in one step.Or when R₂=OEt, the C-3 carboxylate was sponified to give rise to thecorresponding carboxylic acid which was subsequently converted into itscorresponding amide derivatives 12.

A similar method was employed to prepare C-2 unsubstituted C-3 ketoderivatives. Methyl ketone 13 was easily converted into itscorresponding enamine intermediate under heating with microwave. Theintermediate then was coupled with quinone derivative 10 to provide thedesired C-3 ketone compounds.

On the other hand, C-2 ketone derivatives were prepared via theprocedure illustrated in Scheme 5. Ring formation ofo-hydroxybenzaldehyde 16 with a-chloromethylketone in the presence ofweak base such as K2CO3 led to the C-2 ketone benzofuran intermediate17. Subsequent removal of methoxy protecting group and bromination atC-4 and C-6 position resulted in the final product 18In vitro MCD Inhibitory AssayThe conversion of acetyl-CoA from malonyl-CoA was assayed using amodified protocol as previously described by Kim, Y. S. and Kolattukudy,P. E. in 1978 (Arch. Biochem. Biophys 190:585 (1978)). As shown in eq.1-3, the establishment of the kinetic equilibrium between malate/NAD andoxaloacetate/NADH was catalyzed by malic dehydrogenase (eq. 2). Theenzymatic reaction product of MCD, acetyl-CoA, shifted the equilibriumby condensing with oxaloacetate in the presence of citrate synthase (eq.3), which resulted in a continuous generation of NADH from NAD. Theaccumulation of NADH can be continuously followed by monitoring theincrease of fluorescence emission at 460 nm on a fluorescence platereader. The fluorescence plate reader was calibrated using the authenticacetyl-CoA from Sigma. For a typical 96-well plate assay, the increasein the fluorescence emission (λ_(ex)=360 nm, λ_(em)=460 nm, for NADH) ineach well was used to calculate the initial velocity of hMCD. Each 50 μLassay contained 10 mM phosphate buffered saline (Sigma), pH 7.4, 0.05%Tween-20, 25 mM K₂HPO₄—KH₂PO₄ (Sigma), 2 mM Malate (Sigma), 2 mM NAD(Boehringer Mannheim), 0.786 units of MD (Roche Chemicals), 0.028 unitof CS (Roche Chemicals), 5-10 nM hMCD, and varying amounts of MCAsubstrate. Assays were initiated by the addition of MCA, and the rateswere corrected for the background rate determined in the absence ofhMCD.Isolated Working Rat Heart Assay Protocol

Isolated working hearts from male Sprague-Dawley rats (300-350 g) aresubjected to a 60-minute aerobic perfusion period. The working heartsare perfused with 95% O₂, 5% CO₂ with a modified Krebs-Henseleitsolution containing 5 mM glucose; 100 μU/mL insulin; 3% fatty acid-freeBSA; 2.5 mM free Ca²⁺, and 0.4 to 1.2 mmol/L palmitate (Kantor et al.,Circulation Research 86:580-588(2000)). The test compound is added 5minutes before the perfusion period. DMSO (0.05%) is used as control.

Measurement of Glucose Oxidation Rates

Samples were taken at 10-minute intervals for measurements ofexperimental parameters. Glucose oxidation rates are determined by thequantitative collection of ¹⁴CO₂ produced by hearts perfused with buffercontaining [U14]-Glucose (R. Barr and G. Lopaschuk, in “Measurement ofcardiovascular function”, McNeill, J. H. ed., Chapter 2, CRC press, NewYork (1997)). After the perfusion, the ¹⁴CO₂ from the perfusae issubsequently released by injecting 1 mL of perfusate into sealed testtube containing 1 mL of 9N H₂SO4. The tube was sealed with a rubberstopper attached to a scintillation vial containing a piece of filterpapers saturated with 300 μl of hyamine hydroxide. The scintillationvials with filter papers were then removed and Ecolite ScintillationFluid added. Samples were counted by standard procedures as describedabove. Average rates of glucose oxidation for each phase of perfusionare expressed as μmol/min/g dry wt as described above.

Measurement of Fatty Acid Oxidation Rates

Rates of fatty acid oxidation are determined using the same method asdescribed above for glucose oxidation rate measurement using[¹⁴C]palmitate or by the quantitative collection of ³H₂O produced byhearts perfused with buffer containing [5-³H]palmitate (R. Barr and G.Lopaschuk, in “Measurement of cardiovascular function”, McNeill, J. H.ed., Chapter 2, CRC press, New York (1997)). ³H₂O was separated from[5-³H]palmitate by treating 0.5 mL buffer samples with 1.88 mL of amixture of chloroform/methanol (1:2 v:v) and then adding 0.625 mL ofchloroform and 0.625 mL of a 2 M KCl/HCl solution. The sample iscentrifuged for 10 min and aqueous phase was removed and treated with amixture of 1 mL of chloroform, 1 mL of methanol and 0.9 mL KCl/HCl witha ration of 1:1:0.9. The aqueous layer was then counted for total ³H₂Odetermination. This process resulted in greater than 99.7% extractionand separation of ³H₂O from the pamiltate. Average rates of fatty acidoxidation for each phase of perfusion are expressed as nmol/min/g dry wtafter taking consideration the dilution factor.

Active compounds are characterized by an increase in glucose oxidationand/or decrease in fatty acid oxidation as compared to the controlexperiments (DMSO). The compounds that caused statistically significantincreases in glucose oxidation and/or decrease in fatty acid oxidationare considered to be active. Statistical significance was calculatedusing the Student's t test for paired or unpaired samples, asappropriate. The results with P<0.05 are considered to be statisticallysignificant.

TABLE 1 In vitro Enzymatic Inhibitory Activities Examples Ki (nM)CBP-000022880 33.5 CBP-000022880 35.7 CBP-000022902 998.1 CBM-000302109450 CBM-000302150 121 CBM-000302151 1296.9 CBM-000302164 3293.8CBM-000302272 3692.3 CBM-000302300 1653.1 CBM-000302301 315.1CBM-000302323 1561.7 CBM-000302324 2326.1 CBM-000302325 4392.9CBM-000302331 299.2 CBM-000302332 3696.2 CBM-000302333 3433.1CBM-000302335 919.4 CBM-000302336 2808.2 CBM-000302349 1704.9CBM-000302351 2911.3 CBM-000302352 3821 CBM-000302364 4512 CBM-0003023662499.9 CBM-000302381 94.4 CBM-000302382 1431.1 CBM-000302383 1753.6CBM-000302401 224.5 CBM-000302402 195.7 CBM-000302403 4655.1CBM-000302416 2477.1 CBM-000302417 1649.1 CBM-000302418 2158.9CBM-000302420 50.6 CBM-000302421 3208.8 CBM-000302423 1590.5CBM-000302437 3804.3 CBM-000302441 31.6 CBM-000302448 3425.2CBM-000302450 3338.2 CBM-000302452 4671.2 CBM-000302453 5326.3CBM-000302454 1990.1 CBM-000302455 4144.3 CBM-000302456 1116.7CBM-000302457 2343.3 CBM-000302477 2094.7 CBM-000302478 208.9CBM-000302494 755.9 CBM-000302496 1982.6 CBM-000302497 2080.8CBM-000302498 616.2 CBM-000302499 1664.8 CBM-000302501 4812CBM-000302502 3666.6 CBM-000302503 269.1 CBM-000302505 4750.2CBM-000302507 681.1 CBM-000302508 26.7 CBM-000302512 1149.9CBM-000302513 3318.8 CBM-000302528 3630.3 CBM-000302529 1965.7

EXAMPLES

To further illustrate this invention, the following examples areincluded. The examples should not be construed as specifically limitingthe invention. Variations of these examples within the scope of theclaims are within the purview of one skilled in the art are consideredto fall within the scope of the invention as described, and claimedherein. The reader will recognize that the skilled artisan, armed withthe present disclosure, and skill in the art is able to prepare and usethe invention without exhaustive examples.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

¹H nuclear magnetic resonance spectra (NMR) is measured in CDCl₃ orother solvents as indicated by a Varian NMR spectrometer (Unity Plus400, 400 MHz for ¹H) unless otherwise indicated and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane.The peak shapes are denoted as follows, s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet.

The following abbreviations have the indicated meanings:

-   -   Ac=acetyl    -   Bn=benzyl    -   Bz=benzoyl    -   CDI=carbonyl diimidazole    -   CH₂Cl₂=dichloromethane    -   DIBAL=diisobutylaluminum hydride    -   DMAP=4-(dimethylamino)-pyridine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   EDCI or ECAC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide    -   hydrochloric acid    -   ESIMS=electron spray mass spectrometry    -   Et₃N=triethylamine    -   EtOAc=ethyl acetate    -   HMTA=hexamethylenetetramine    -   LDA=lithium diisopropylamide    -   LHDMS=lithium bis(trimethylsilyl)amide    -   MgSO₄=magnesium sulfate    -   NaH=sodium hydride    -   NBS=N-bromosuccinimide    -   NCS=N-chlorosuccinimide    -   NH₄Cl=ammonium chloride    -   Ph=phenyl    -   Py=pyridinyl    -   r.t.=room temperature    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography    -   Tf₂O=triflic anhydride    -   Alkyl group abbreviations    -   Me=methyl    -   Et=ethyl    -   n-Pr=normal propyl    -   i-Pr=isopropyl    -   n-Bu=normal butyl    -   i-Bu=isobutyl    -   t-Bu=tertiary butyl    -   s-Bu=seconday butyl    -   c-Hex=cyclohexyl

Example 1 Preparation of 4,6-dibromo-2-carboxy-5-hydroxybenzofuran

Step 1: Preparation of 2-carboxy-5-hydroxybenzofuran2-Carboxy-5-methoxybenzofuran (1.0 g, 5.2 mmol) was dissolved inanhydrous dichloromethane (25 ml) and cooled to −78° C. A 1 M solutionof borontribromide (15.6 ml) in dichloromethane was added slowly. Thereaction mixture was allowed to warm to ambient temperature under anatmosphere of nitrogen, and stirred 4 hours. The solution was quenchedwith aqueous ammonium chloride (20 ml) and extracted with ethyl acetate.The aqueous layer was washed with water and dried over sodium sulfate.0.9 g (100%) of crude product was obtained. ¹H NMR(CD₃OD) δ=6.84 (dd,1H), 6.95 (d, 1H), 7.17 (s, 1H), 7.32 (d, 1H).Step 2: Preparation of 4,6-dibromo-2-carboxy-5-hydroxybenzofuran2-carboxy-5-hydroxybenzofuran (980 mg, 5.50 mmol) and potassium acetate(1.10 g, 11.21 mmol) were dissolved in acetic acid (30 ml) and cooled to0° C. Bromine (845 μl, 16.50 mmol) was dissolved in acetic acid (2 ml)and added slowly to the above solution. The reaction mixture was allowedto warm to ambient temperature under an atmosphere of nitrogen, andstirred 2.5 hours. Water (20 ml) was then added to the solution and thereaction quenched upon the addition of Na₂S₂O₃-5H₂O (260 mg). Theaqueous solution was extracted with diethyl ether, and the organic layerwashed with aqueous sodium thiosulfate and dried over sodium sulfate.Concentration in vacuo yielded a tan solid which was washed with hexanesto yield 1.04 g (56%). ¹H NMR (CD₃OD) δ=7.39 (s, 1H), 7.82 (s, 1H).

Example 2 Preparation of 4,6-dibromo-3-carboxy-5-hydroxybenzofuran

Step 1: Preparation of 3-bromo-2-carboxy-5-methoxybenzofuran2-Carboxy-5-methoxybenzofuran (2.00 g, 10.41 mmol) was suspended incarbon disulfide (70 ml) and bromine (1.18 ml, 22.96 mmol) was added.The mixture was refluxed 48 hours. The crude product was isolated byevaporation of solvent in vacuo. 2.64 g (96%). ¹H NMR (CD₃OD) δ3.94 (s,3H), 7.28 (d, 1H), 7.48 (s, 1H), 7.57 (d, 1 H).Step 2: Preparation of 3-bromo-5-methoxybenzofuran3-Bromo-2-carboxy-5-methoxybenzofuran (1.36 g, 5.02 mmol), powderedcopper (371 mg, 5.84 mmol), and quinoline (16 ml) were combined andheated to 210° C. for 0.5 hours. After the mixture cooled to ambienttemperature the solids were removed by filtration through celite. Thefiltrate was diluted with dichloromethane and washed three times with 1M aqueous hydrochloric acid, once with aqueous sodium bicarbonate, andonce with brine. The organic phase was dried over sodium sulfate,concentrated in vacuo, and purified by column chromatography (SiO₂ gel,6:1 hexanes/ethyl acetate) to yield 708 mg (62%). ¹H NMR (CDCl₃) δ3.94(s, 3H), 6.79 (d, 1H), 6.96 (s, 1 H), 7.34 (dd, 1H), 7.64 (d, 1H).Step 3: Preparation of 3-carboxy-5-methoxybenzofuran.A 2.5 M solution of n-butyl lithium (5.6 ml, 2.24 mmol) in hexanes wasadded dropwise to a solution of 3-bromo-5-methoxybenzofuran (483 mg,2.13 mmol) in anhydrous THF at −78° C. the cooled reaction mixture wasstirred for 0.5 hours under an atmosphere of nitrogen. Powdered CO₂(s)was added and the mixture stirred an additional 0.5 hours beforeallowing it to warm to ambient temperature. After 0.5 hours the reactionwas quenched with 2 M aqueous hydrochloric acid, concentrated in vacuo,and extracted with ethyl acetate. The organic layer was washed withwater and dried over sodium sulfate. Purification by preparative TLC(3:2 hexanes/ethyl acetate) yielded 113 mg (9%). ¹H NMR(CD₃OD) δ3.84 (s,3H), 6.94 (dd, 1H), 7.42 (d, 1H), 7.49 (d, 1H), 8.35 (s, 1H).Step 4: Preparation of 3-carboxy-5-hydroxybenzofuran3-carboxy-5-methoxybenzofuran (128 mg, 0.666 mmol) was dissolved inanhydrous dichloromethane (25 ml) and cooled to −78° C. A 1 M solutionof borontribromide (15.6 ml) in dichloromethane was added slowly. Thereaction mixture was allowed to warm to ambient temperature under anatmosphere of nitrogen, and stirred 3 hours. The solution was quenchedwith aqueous ammonium chloride (20 ml) and extracted with ethyl acetate.The aqueous layer was washed with water and dried over sodium sulfate.106 mg (89%) of crude product was obtained. ¹H NMR(CD₃OD) δ6.84 (dd,1H), 7.36 (d, 1H), 7.39 (d, 1H), 8.32 (s, 1H).Step 5: Preparation of 4,6-dibromo-3-carboxy-5-hydroxybenzofuran3-carboxy-5-hydroxybenzofuran (100 mg, 0.561 mmol) and potassium acetate(83 mg, 0.842 mmol) were dissolved in acetic acid (10 ml) and cooled to0° C. Bromine (86 μl, 1.680 mmol) was and added slowly to the abovesolution and the reaction mixture was allowed to warm to ambienttemperature under an atmosphere of nitrogen, stirring 3 hours. Thereaction was quenched with aqueous sodium thiosulfate, extracted withethyl acetate, washed with water and dried over sodium sulfate.Concentration in vacuo yielded a tan solid which was washed with hexanesto yield 155 mg (82%). ¹H NMR(CD₃OD) δ 7.83 (s, 1H), 8.37 (s, 1H).

Example 3 Preparation ofN-alkyl-4,6-dibromo-5-hydroxybenzofuran-2-carboxamides

Step 1: Preparation ofN-1,5-dimethylhexyl-4,6-dibromo-5-hydroxybenzofuran-2-carboxamideCombined 4,6-dibromo-2-carboxy-5-hydroxybenzofuran (16 mg, 0.048 mmol),1,5-dimethylhexylamine (9 mg, 0.052 mmol), HBTU (33 mg, 0.062 mmol), andN,N-diisopropylethylamine (26 μl, 0.144 mmol) in DMF (2 ml) at 0° C. Themixture was stirred 2 hours, concentrated in vacuo and purified bypreparative TLC (50% ethyl acetate, 50% hexanes) to yield 3.5 mg (16%).¹H NMR (CDCI₃) δ 0.84 (m, 6H), 1.09-1.36 (m, 5H), 1.50-1.60 (m, 5H),4.09 (m, 1H), 6.29 (d, 1H), 7.38 (s, 1H), 7.64 (s, 1H).

Example 4 Preparation ofN-alkyl-4,6-dibromo-5-hydroxybenzofuran-2-carboxamides

All the compounds listed in Table 1 were prepared according to theprocedure described in the above examples.

TABLE 1 N-alkyl-4,6-dibromo-5-hydroxybenzofuran-2-carboxamides.

Examples R1 R2 4-1 1-Me-2-(CO2tBu)-ethyl H 4-2 1,5-dimethylhexyl H 4-3cyclohexylmethyl H 4-4 4-(3-Me-pentyl)-Ph H 4-54-(4,4,4-trifluorobutyl)-Ph H 4-6 OMe Me 4-7 4-[CH2(CO2Et)]—Ph H 4-82-(CO2tBu)-ethyl H 4-9 1-iPr-2-(CO2tBu)-ethyl H 4-10 2,5-diMeO—PhCH2 H4-11 2,5-diMeO—PhCH2CH2 H 4-12 4-nBuO—Ph H 4-13 furan-2-ylmethyl H 4-142,5-diMeO—PhCONH H 4-15 Ph Me 4-16 4-(CO2Me)—Ph Me 4-17 (CO2tBu)CH2 Me4-18 cyclohexyl H 4-19 3,4,5-triMeO—Ph H 4-20 4-Me—Ph H 4-21 Ph H 4-224-(NCCH2)-Ph H 4-23 3,5-diBr-4-OH—Ph H 4-24 PhCH2CH2 Me 4-25 Ph iPr 4-26PhCH2 Me 4-27 iBu Me 4-28 (CO2Et)CH2 Me 4-29 (CO2tBu)CH2 H 4-30 4-MeO—PhMe 4-31 4-CF3-PhCH2 Me 4-32 4-CF3O—PhCH2 Me 4-33 4-(CO2Me)—PhCH2 Me 4-34(CO2tBu)CH2 tBu 4-35 3,5-diMeO—Ph H 4-36 (CO2tBu)CH2 iPr 4-372,5-diMeO—Ph H 4-38 2,3-diMeO—Ph H 4-39 4-tBu—Ph H 4-40 3,4-diMeO—Ph H4-41 1,3-dioxolanylmethyl Me 4-42 n-pentyl Me 4-432-(N,N-dimethyl)-ethyl Me 4-44 2-(N,N-diethyl)-ethyl Me 4-452-(N,N-dimethyl)-propyl Me 4-46 2-Cl—Ph Me 4-47 4-Cl—Ph Me 4-48 2-Me—PhMe 4-49 4-Me—Ph Me 4-50 furan-2-ylmethyl Me 4-51 napthalyl Me 4-524-MeO—Ph Me 4-53 3,4-diMeO—PhCH2CH2 Me 4-54 3,4-diCl—Ph Me 4-553,4,5-triMeO—PhCH2 Me 4-56 3-Me—Ph Me 4-57 2-(6-MeO)-pyridinyl Me 4-581,1-dimethyl-2-(CO2tBu)ethyl H

Example 5 Preparation ofN-alkyl-4,6-dibromo-5-hydroxybenzofuran-3-carboxamides

Step 1: Preparation ofN-(3,4-dimethoxyphenyl)-4,6-dibromo-5-hydroxybenzofuran-3-carboxamideCombined 4,6-dibromo-3-carboxy-5-hydroxybenzofuran (60 mg, 0.179 mmol),3,4-dimethoxyaniline (27 mg, 0.179 mmol), and EDC (41 mg, 0.215 mmol inTHF (5 ml) and stirred overnight. The mixture was diluted with water,extracted with ethyl acetate, dried over sodium sulfate, andconcentrated in vacuo. The crude material was purified by preparativeTLC (2:1 hexanes/ethyl acetate) to yield 9 mg (23%). ¹H NMR(CDCl₃) δ3.87 (s, 3H), 3.90 (s, 3H), 5.96 (s, 1H), 6.83 (d, 1H), 6.99 (d, 1H),7.44 (d, 1H), 7.72 (m, 2H), 8.05 (s, 1H); ESIMS: m/z470 (M-H).

Example 6 Preparation ofN-alkyl-4,6-dibromo-5-hydroxybenzofuran-3-carboxamides

All compounds listed in Table 2 were prepared according to the proceduredescribed in the above examples.

TABLE 2 N-alkyl-4,6-dibromo-5-hydroxybenzofuran-3-carboxamides.

Examples R1 R2 6-1 (CO2tBu)-methyl Me 6-2 Ph H 6-3 4-(CO2Me)—Ph Me 6-43,4,5-triMeO—Ph H 6-5 3,5-diMeO—Ph H 6-6 3,4-diMeO—Ph H 6-7 4-CF3O—Ph Me6-8 4-CF3O—PhCH2 H 6-9 3,4,5-triMeO—PhCH2 Me 6-10 H 6-11 (CO2tBu)-methyliPr 6-12 2-[2-Me—(CO2tBu)]-ethyl H 6-13 2-(CO2tBu)-ethyl H 6-143-(iPrO)-propyl H

Example 7 Preparation of 4,6-dibromo-5-hydroxybenzofuran-3-ketones

Step 1: Preparation of4,6-dibromo-3-(2,5-dimethoxybenzoyl)-5-hydroxybenzofuranN,N-dimethylformamide dimethyl acetal (141 μl, 1.06 mmol) and2,5-dimethoxyacetophenone (161 μl, 1.01 mmol) were microwaved togetherat 150° C. for two hours. 2,6-dibromo-p-benzoquinone (266 mg, 1.00 mmol)was added in acetic acid (0.5 ml) and the mixture stirred overnight. Thereaction was concentrated in vacuo and purified by preparative TLC (50%ethyl acetate, 50% hexanes) to yield 37 mg (8%). ¹H NMR (CD₃OD) δ3.55(s, 3H), 3.77 (s, 3H), 6.90 (s, 1H), 7.03 (d, 1H), 7.16 (m, 2H), 7.81(s, 1H), 8.01 (s, 1H); ESIMS: m/z 455 (M-H).

Example 8 Preparation of 4,6-dibromo-5-hydroxybenzofuran-3-ketones

All compounds listed in Table 3 were prepared according to the proceduredescribed in the above examples.

TABLE 3 4,6-dibromo-5-hydroxybenzofuran-3-ketones. Example R1 8-1 2,5-diMeO—Ph 8-2  Ph 8-3  2-F-5-CF3—Ph 8-4  2-OH-5-Br—Ph 8-5 3,4,5-triMeO—Ph 8-6  1-napthyl 8-7  3,5-diMeO—Ph 8-8 1,4-benzodioxan-6-yl 8-9  4-Me—Ph 8-10 4-MeO—Ph 8-11 4-tBu—Ph 8-123-MeO—Ph 8-13 2-pyridinyl 8-14 2-(4-MeO—PhO)—Et 8-15 Me 8-16 3-NO2—Ph8-17 2-Br—Ph 8-18 3,5-di(PhCH2O)—Ph 8-19 4-CF3—Ph 8-20 4-F—Ph 8-214-(PhSO2)—Ph 8-22 4-pyridinyl 8-23 3-pyridinyl 8-24 4-Cl—Ph 8-25 3-Cl—Ph8-26 6-[1,3-thiazolo(3,2-A)pyrimidinone] 8-27 2-(3-Me-benzothiophene)8-28 2-(1,2,4-triazol-1-yl)-ethyl 8-29 indol-3-yl 8-30N—Me-1,3-thiazol-2-amine

Example 9 Preparation of 4,6-dibromo-5-hydroxybenzofuran-2-ketones

Step 1: Preparation of 2-benzoyl-5-methoxybenzofuran2-hydroxy-5-methoxybenzaldehyde (164 μl, 1.31 mmol),a-chloroacetophenone (203 mg, 1.31 mmol), and potassium carbonate (217mg, 1.57 mmol) were heated in 2-butanone (10 ml) at 80° C. for 7 hours.The solvent was removed in vacuo and the residue was dissolved in ethylacetate. The organic solution was washed twice with 2 M aqueous sodiumhydroxide, once with brine, and dried over sodium sulfate to yield 315mg (95%) of crude product. ¹H NMR (CDCl₃) δ3.87 (s, 3H), 7.12 (s, 1H),7.14 (d, 1H), 7.53-7.56 (m, 3H), 7.65 (m, 1H), 8.04 (d, 2H).Step 2: Preparation of 2-benzoyl-5-hydroxybenzofuran2-benzoyl-5-methoxybenzofuran (100 mg, 0.396 mmol) was dissolved inanhydrous dichloromethane (10 ml) and cooled to −78° C. A 1 M solutionof borontribromide (1.2 ml) in dichloromethane was added slowly. Thereaction mixture was allowed to warm to ambient temperature under anatmosphere of nitrogen, and stirred 3 hours. The solution was quenchedwith aqueous ammonium chloride (10 ml) and extracted with ethyl acetate.The aqueous layer was washed with water and dried over sodium sulfate.69 mg (73%) of crude product was obtained. ¹H NMR (CD₃OD) δ 7.04 (dd,1H), 7.09 (d, 1H), 7.45 (d, 1H), 7.52 (s, 1H), 7.55 (m, 2H), 7.67 (m,1H), 8.01 (m, 2H).Step 3: Preparation of 2-benzoyl-4,6-dibromo-5-hydroxybenzofuran2-benzoyl-5-hydroxybenzofuran (60 mg, 0.252 mmol) and potassium acetate(37 mg, 0.378 mmol) were dissolved in acetic acid (10 ml) and cooled to0° C. Bromine (39 μl, 0.756 mmol) was and added slowly to the abovesolution and the reaction mixture was allowed to warm to ambienttemperature under an atmosphere of nitrogen, stirring 3 hours. Thereaction was quenched with aqueous sodium thiosulfate, extracted withethyl acetate, washed with water and dried over sodium sulfate.Concentration in vacuo yielded a tan solid which was washed with hexanesto yield 7 mg (7%). ¹H NMR(CDCl₃) δ5.91 (s, 1H), 7.44 (s, 1H), 7.57 (appt, 2H), 7.68 (app t, 1H), 7.81 (s, 1H), 8.03 (m, 2H). ESIMS: m/z 395(M-H).

Example 10 Preparation of 4,6-dibromo-5-hydroxybenzofuran-2-ketones

All the compounds listed in Table 4 were prepared according to theprocedure described in the above examples.

TABLE 4 4,6-dibromo-5-hydroxybenzofuran-2-ketones. Examples R1 10-14-Me—Ph 10-2 Ph 10-3 3-NO2-Ph

1. A compound represented by the following structural formula:

wherein R₁ is —COR₅ or —CONR₅R₆; R3 and R4 are the same and are bromo orchloro; R₅ is C₁-C₈ alkyl; cyclohexyl; cyclohexylmethyl; benzyl;phenethyl; naphthyl; furanylmethyl; pyridyl; methoxypyridyl;dioxolanylmethyl; benzodioxolanyl; thiazolopyrimidinonyl;methylbenzothienyl; triazolylethyl; indolyl; N-methylthiazolylamino;dimethoxyphenylcarbonylamino; a C₁-C₃ alkyl substituted with: onesubstituent selected from C₁-C₄ alkoxycarbonyl, C₁-C₃ alkoxy, phenoxy,N,N-dimethylamino, and N,N-diethylamino, or two substituents selectedfrom C₁-C₃ alkyl and t-butoxycarbonyl, or one methoxy and one phenoxy,or three substituents which are two methyl and one t-butoxycarbonyl; aphenyl, benzyl or phenethyl where the phenyl ring is substituted withone substituent selected from halo, C₁-C₆ alkyl, hydroxyl, C₁-C₄ alkoxy,C₁-C₄ trifluoroalkyl, trifluoromethoxy, nitro, methoxycarbonyl,ethoxycarbonylmethyl, cyanomethyl and phenylsulfonyl, or twosubstituents selected from halo, methoxy and benzyloxy, or one halo andone trifluoromethyl or hydroxyl, or three substituents selected frommethoxy or one hydroxyl and two halo; provided that, when R₅ is phenylsubstituted with one substituent, the substituent is not 4-methyl or4-methoxy; R₆ is hydrogen; or C₁-C₄ alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1, wherein the compoundis represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 3. A compound of claim 1,wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof. 4.(4,6-dibromo-5-hydroxy-1-benzofuran-2-yl)(phenyl)methanone;4,6-dibromo-N-(4-tert-butylphenyl)-5-hydroxy-1-benzofuran-2-carboxamide;4,6-dibromo-N-(3,4-dimethoxyphenyl)-5-hydroxy-1-benzofuran-2-carboxamide;4,6-dibromo-N-(1,3-dioxolan-2-ylmethyl)-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-5-hydroxy-N-methyl-N-pentyl-1-benzofuran-2-carboxamide;4,6-dibromo-N-[2-(dimethylamino)ethyl]-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-N-[2-(diethylamino)ethyl]-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-N-[3-(dimethylamino)proyl]-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-5-hydroxy-N-methyl-N-(2-methylphenyl)-1-benzofuran-2-carboxamide;4,6-dibromo-N-(2-furylmethyl)-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide:4,6-dibromo-N-(2-chlorophenyl)-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-N-(4-chlorophenyl)-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-5-hydroxy-N-methyl-N-(1-naphthylmethyl)-1-benzofuran-2-carboxamide;4,6-dibromo-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-N-(3,4-dichlorophenyl)-5-hydroxy-N-methyl-1-benzofuran-2-carboxamide;4,6-dibromo-5-hydroxy-N-methyl-N-(3,4,5-trimethoxybenzyl)-1-benzofuran-2-carboxamide;4,6-dibromo-5-hydroxy-N-methyl-N-(3-methylphenyl)-1-benzofuran-2-carboxamide;4,6-dibromo-5-hydroxy-N-(6-methoxypyridin-2-yl)-N-methyl-1-benzofuran-2-carboxamide;tert-butyl3-{[(4,6-dibromo-5-hydroxy-1-benzofuran-2-yl)carbonyl]amino}-3-methylbutanoate;4,6-dibromo-N-(3,4-dimethoxyphenyl)-5-hydroxy-1-benzofuran-3-carboxamide;4,6-dibromo-5-hydroxy-N-methyl-N-[4-(trifluoromethoxy)phenyl]-1-benzofuran-3-carboxamide;4,6-dibromo-5-hydroxy-N-(4-methoxybenzyl)-1-benzofuran-3-carboxamide;4,6-dibromo-5-hydroxy-N-methyl-N-(3,4,5-trimethoxybenzyl)-1-benzofuran-3-carboxamide;4,6-dibromo-5-hydroxy-N-[4-(trifluoromethoxy)phenyl]-1-benzofuran-3-carboxamide;tert-butylN-[(4,6,dibromo-5-hydroxy-1-benzofuran-3-yl)carbonyl]-N-isopropylglycinate;tert-butyl3-{[4,6-dibromo-5-hydroxy-1-benzofuran-3-yl)carbonyl]amino}-3-methylbutanoate;(4,6-dibromo-5-hydroxy-1-benzofuran-3-yl)carbonylN-[3-(dimethylamino)propyl]-N′-ethylimidocarbamate;(4,6-dibromo-5-hydroxy-1-benzofuran-2-yl)(3-nitrophenyl)methanone;tert-butyl3-{[(4,6-dibromo-5-hydroxy-1-benzofuran-3-yl)carbonyl]amino}butanoate;or4,6-dibromo-5-hydroxy-N-(3-isopropoxypropyl)-1-benzofuran-3-carboxamideor a pharmaceutically acceptable salt thereof.
 5. A compositioncomprising a pharmaceutically acceptable carrier and a compound of claim1 or claim 4.